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CD8 NK/T Cells and the Phylogeny of Cellular Immunity

CD8 NK/T 细胞和细胞免疫的系统发育

基本信息

批准号：
0136536
负责人：
Jacques Robert
金额：
$ 52.53万
依托单位：
University of Rochester
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2006-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=0136536&HistoricalAwards=false
关键词：
CD8 NK Cells Phylogeny Cellular

项目摘要

CD8 cytotoxic T-lymphocytes (CTL) recognize and kill targets that express antigenic peptides in the context of major histocompatibility complex (MHC) class I molecules. As such, CTL are crucially involved in the generation of adaptive immunity against viruses and tumors. Natural killer (NK) cells play an active role in innate immunity by detecting and killing virally-infected or tumor cells that have down-regulated their surface MHC class I molecules thereby escaping surveillance by the adaptive immune system. Growing evidence suggests that some immune responses are mediated by CTL expressing NK-associated molecules (CD8/NK T-cells). The biology and physiological significance of the complexity and heterogeneity of NK-associated molecules and their expression by different effectors (e.g. CTL) is unclear. Since it is now well established in several species, including frogs, that certain heat shock proteins (e.g. gp96 or hsp70) elicit both adaptive CD8 T-cell mediated responses against the antigenic peptides they chaperone, and innate immune responses, it will be of significance to explore, for the first time, the extent to which this putative ancestral system of hsp-generated immunity may involve CTL that express NK-associated molecules. In addition, an unequivocal characterization of NK/T-cells in an amphibian that occupies a pivotal position in the evolution of vertebrates would support the hypothesis that CD8 NK/T-cells represent an important evolutionary step that bridges the innate and adaptive immune systems. This finding would also attest of the importance of this cell type in immunity of mammals. Finally, a better knowledge of cell-mediated cytotoxicity in Xenopus may have crucial implication with respect to understanding putative defects in the immune defense systems used against those viral pathogens that are causing world-wide declines of amphibian populations. The overall goal of this project is to take advantage of our Xenopus model to assess, from an evolutionary perspective, the role of CD8 NK/T cells, both in vitro and in vivo, in innate and adaptive immune responses to tumor, viral, and minor histocompatibility antigens as well as to explore the idea that T-cells co-expressing CD8 and NK markers (CD8 NK/T-cells) are phylogenetically early mediators of cellular immunity. Natural killer and cytotoxic T-lymphocytes are two important types of immune cells involved in defense against virus infections and tumor. Recent studies suggest the existence of a novel cell type with intermediate characteristics. The goal of the research program is to use the frog Xenopus rather than mice as a model system to better understand the role of this new type of immune cell in immune defense against cancer and virus infections from an evolutionary perspective.

CD 8细胞毒性T淋巴细胞（CTL）识别并杀死在主要组织相容性复合体（MHC）I类分子背景下表达抗原肽的靶标。因此，CTL在产生针对病毒和肿瘤的适应性免疫中至关重要。自然杀伤（NK）细胞通过检测和杀死病毒感染的细胞或肿瘤细胞在先天免疫中发挥积极作用，所述病毒感染的细胞或肿瘤细胞已经下调其表面MHC I类分子，从而逃避适应性免疫系统的监视。越来越多的证据表明，一些免疫应答是由表达NK相关分子（CD 8/NK T细胞）的CTL介导的。NK相关分子的复杂性和异质性及其通过不同效应物（例如CTL）表达的生物学和生理学意义尚不清楚。由于现在在包括青蛙在内的几个物种中已经很好地确定了某些热休克蛋白（例如gp 96或hsp 70）引起针对它们伴侣的抗原肽的适应性CD 8 T细胞介导的应答和先天免疫应答，这将是有意义的，首次探索，这种假定的hsp产生免疫的祖先系统可能涉及表达NK相关分子的CTL的程度。此外，在脊椎动物进化中占据关键地位的两栖动物中NK/T细胞的明确表征将支持CD 8 NK/T细胞代表连接先天性和适应性免疫系统的重要进化步骤的假设。这一发现也证明了这种细胞类型在哺乳动物免疫中的重要性。最后，更好地了解细胞介导的细胞毒性在非洲爪蟾可能有至关重要的意义，了解假定的缺陷，用于对那些病毒病原体，导致世界范围内的两栖动物种群下降的免疫防御系统。本项目的总体目标是利用我们的非洲爪蟾模型，从进化的角度评估CD 8 NK/T细胞在体外和体内对肿瘤、病毒、和次要组织相容性抗原，并探讨共表达CD 8和NK标记的T细胞（CD 8 NK/T细胞）是细胞免疫的遗传学早期介质。自然杀伤和细胞毒性T淋巴细胞是两种重要的免疫细胞，参与防御病毒感染和肿瘤。最近的研究表明存在一种具有中间特征的新型细胞类型。该研究计划的目标是使用青蛙爪蟾而不是小鼠作为模型系统，以便从进化的角度更好地了解这种新型免疫细胞在免疫防御癌症和病毒感染中的作用。